J-carbamyl pseudotropine and process



United States Patent 3,073,830 Patented J an. 15, 71963 "ice 3,073 830 S-CARBAMYL PSEUDOTIIOPINE AND PROCESS Sydney Archer, Bethlehem, and Malcolm R. Bell, East Greenhush, N.Y., assignors to Sterling Drug Inc., New

This invention relates to intermediates in the preparation of compounds having the formula CH- CH2 1 (1) (2) O O O R" I I\ OHz-OH-CHa COO-lower-alkyl CHr-CHCHz OH I R Mg-halide -i ax CH2'CHCH2 CONE:

III

VII (R=E or lower-alkoxy) In this application the compounds of Formula III and their preparation are claimed.

A 3-hydroxy-3-carbo-lower-alkoxy-8-R-nortrop ane of structure II is converted to the corresponding amide, 3- hydroxy-3-carbamyl-8-R-nortropane (III), by treating with sodium amide in liquid ammonia. The amide III is then subjected to a Grignard reaction With a loweralkylmagnesium halide, the reaction stopping readily at the ketone stage to give a 3-hydroxy-3-lower-alkanoyl- 8-R-nortropane (IV). Thelatter is then subjected to a second Grignard reaction with phenyllithium, phenylmagnesium halide or a 3-lower-alkoxyphenylmagnesium halide to produce a 3-hydroxy-3-[lower-alkyl(monocarbocyclic aryl)hydroxymethyl]-8-R nortropane (V).

The diol V is then converted to the desired 3-(monocarbocyclic aryl)-3-lower alkanoyl-8-R-nortropane (VI) by treatment with zinc chloride and acetic anhydride at room temperature for ten or more hours.

The ketone V1 is then converted to its oxime, a 3- (monocarbocyclic aryl)-3-( 1-isor1itroso-lower alkyl')-8- R-nortropane (VH), by treatment with hydroxylamine.

The oxime VII is then subjected to the Beckmann rearrangement by heating it with hydrochloric and acetic acid at about C. and the structure I (R=H) is produced.

The molecular structures of the novel compounds herein disclosed are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses for representative examples. The structures are further confirmed by ultraviolet and infrared spectral data proving the presence of the various functional groups.

The compounds of our invention having the general Formula I possess valuable pharmacodynamic properties, in particular, analgesic activity.

The following examples will further illustrate the invention without the latter being limited thereby.

EXAMPLE 1 3-carbamylpseudotropine [111; R is CH ].To a solution of sodium amide, which had been prepared from 14 g. of sodium and a few crystals of ferric nitrate in 1 liter of liquid ammonia, was added 2-0 g. of a-ecgonine methyl ester (3-hydroXy-3-carbomethoxytropane). The reaction mixture was stirred at room temperature until the ammonia had evaporated, and the residue was 'decomposed by dropwise addition of ml. of water. The aqueous phase was saturated with solid potassium carbonate and extracted several times with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give a colorless crystalline residue. The residue was triturated with ml. of absolute ether to give 16.0 g. of 3-carbamylpseudotropine, M.P. 155.8159.2 C. (corn).

Analysis.Calcd. for C H N O C, 58.68; H, 8.76;

N, 15.21. Found: C, 58.85; H, 8.69; N, 15.19.

EXAMPLE 2 addition of 840 ml. of concentrated hydrochloric acid.

After standing for three hours at :room temperature, the aqueous phase was made basic with an excess of solid potassium carbonate, and the solid which precipitated was collected by filtration and extracted twice with 3 liter portions of boiling chloroform. The aqueous filtrate was extracted five times with chloroform. The combined chloroform extracts were dried over anhydrous sodium sulfate and concentrated to yield 72 g. of crystalline solid. The latter was extracted with 1.5 liters of boiling hexane, and concentration of the extracts and cooling caused separation of 29.5 g. of 3-propionylpseudotropine, M.P. 120.6-123.4 C. (corr.) when recrystallized from hexane.

Analysis.--Calcd. for C H NO C, 66.97; H, 9.71; N, 7.10. Found: C, 67.29; H, 9.61; N, 6.94.

EXAMPLE 3 3 (ethylphenylhydroxymethyl)pseudotropine hydrochloride [V; R is CH R is H, R is C H ].-To a solution of phenyllithium, prepared from 31.4 g. of bromobenzene and 2.8 g. of lithium wire in 500 m1. of ether, was added all at once a warm solution of 4.0 g. of 3-propionylpseudotropine in 150 ml. of tetrahydrofuran. After stirring and refluxing for one and one-half hours, the reaction mixture was cooled and hydrolyzed by the addition of 150 ml. of water. The aqeuous phase .was extracted twice with ether, and the ether extracts were dried over anhydrous sodium sulfate and concentrated to drymess in vacuo. The residue was dissolved in methylene dichloride, the solution dried over anhydrous sodium sulfate and concentrated to give 6.5 g. of a light yellow oil which crystallized upon standing at room temperature. The latter was dissolved in acetone and a slight excess of alcoholic hydrogen chloride was added. The salt which separated was collected by filtration, giving 5.0 g. of 3-(ethylphenylhydroxymethyl)pseudotropine hydrochloride, M.P. 212.4213.8 C. (corr.) when recrystallized from a methanol-ether mixture.

Analysis.-Calcd. for C H NO .HCl: C, 65.48; H, 8.40; C], 11.38. Found: C, 65.59; H, 8.44; Cl, 11.23.

EXAMPLE 4 3-phenyl-i-propionyltropane hydrochloride [VI; R is CH R is H, R is C H ].A solution of 3.3 g. of 3- (ethylphenylhydroxymethyl)pseudctropine hydrochlochloride and g. of fused, powdered zinc chloride in 30 ml. of acetic anhydride was stirred at room temperature for fifteen hours. The reaction mixture was poured into an excess of cold aqueous sodium hydroxide and the product was extracted with methylene dichloride. The extracts were dried and concentrated, and the residue was dissolved in 30 ml. of acetone and treated with an excess of alcoholic hydrogen chloride, whereupon there separted 2.2 g. of 3-phenyl-3-propionyltropane hydrochloride, M.P. 273.2-275.8 C. (corn) when recrystallized from a methanol-ether mixture.

Analysis-Calm. for C H NO.HCl: C, 69.49; H, 8.23; Cl, 12.07. Found: C, 69.26; H, 8.06; CI, 12.02.

EXAMPLE 5 3-phenyl-3-c'arboxytropane hydrochloride [1; R is CH R and R" are H, fi-series] can be prepared by heating 3-phenyl 3 (l-isonitrosopropyl)tropane hydrochloride with acetic acid saturated with hydrogen chloride.

4 EXAMPLE 7 3- [ethyl m-anisyl) hydroxymethyl] pseudotropine hydrochloride [V; R is CH R is OCH R is C H To a stirred solution of m-anisylmagnesium bromide prepared from 118 g. of m-bromoanisole and 15.3 g. of magnesium in 1 liter of ether under nitrogen was rapidly added a solution of 15.0 g. of 3-propionylpseudotropine in 250 ml. of tetrahydrofuran. The reaction mixture was refluxed and stirred for three hours, left at room temperature for fifteen hours and then poured into a cold solution of 66 ml. of concentrated hydrochloric acid in 400 ml. of water. The aqueous phase was made basic with solid potassium carbonate, and the inorganic salts were removed by filtration and washed with methylene dichloride. The filtrate was extracted with methylene dichloride and the combined methylene dichloride washings and extracts were dried and concentrated in vacuo. The residue was dissolved in acetone and treated with an excess of ethanolic hydrogen chloride whereupon there separated 14.5 g. of 3-[ethyl(m-anisyl)hydroxymethyl] pseudotropine hydrochloride, M.P. 245245.5 C. (dec.) (uncorr.) after recrystallization from a methanol-ether mixture.

Analysis.-Calcd. for C H NO .HCl: C, 63.23; H, 8.25; CI, 10.37. Found: C, 63.59; H, 8.17; Cl, 10.15.

EXAMPLE 8 3-(m-anisyl)-3-propi0nyltr0pane hydrochloride [VI; R is CH R is OCH R is C H was prepared from 14.2 g. of S-[ethyl(m-anisyl)hydroxymethylJpseudotropine hydrochloride and 28.4 g. of zinc chloride in 280 m1. of acetic anhydride according to the manipulative procedure described above in Example 4. There was thus obtained 7.9 g. of 3-(m-anisyl)-3-propionyltropane hydrochloride, M.P. 2375 2385 C. (uncorr.) when recrystallized first from a methanol-ether mixture and then from an isopropyl alcohol-ether mixture.

Analysis.-Ca1cd. for C H NO .HCl: C, 66.75; H, 8.09; Cl, 10.95. Found: C, 66.94; H, 8.07; Cl 10.97.

EXAMPLE 9 3- (m-anis yl) -3- (I-isonitrosopropyl) tropane hydrochlochloride [VlI; R is CH R is OCH R' is C H can be prepared by heating S-(m-anisyl)-3-propionyltropane hydrochloride and hydroxylamine hydrochloride in pyridine-ethanol solution.

EXAMPLE 10 3-(m-anisyl)-3-carboxytropane hydrochloride [1; R is CH R is OCH R" is H] can be prepared by heating B-(m-anisyl)-3-(m-anisyl) 3 (1-isonitrosopropyl)tropane hydrochloride in acetic acid saturated with hydrogen chloride.

This application is a division of our copending applica tion, Serial No. 1388, filed January 8, 1960, which in turn is a division of our copending application, Serial No. 731,857, filed April 30, 1958.

We claim:

1. 3-carbamylpseudotropine.

2. The process for preparing 3-carbamylpseudotropine which comprises treating a 3-hydroxy-3carbo-loweralkoxytropane with sodium amide in liquid ammonia.

No references cited.

UNITE STATES PATENT OFFICE QB HEICATE 0F CORRECTIN Patent No, S OYS SSO January l5fl963 f Sydney Archer et ale It is hereby certified that error en't requiring correction and that the s corrected below.

appears in the above numbered pataid Letters Patent should read as Column 2 line 21 for (VH) read M (VII) column 4 3-:-(m--anisyl) Signed and sealed this lei; day of October 1963,

(SEAL) Attest:

ERNEST W0 SWIDER DAVID L. LADD Commissioner of Patents Attesting Officer 

1. 3-CARBAMYLPSEUDOTROPINE. 